Principal Investigator/Program Director (Last, First, Middle: Ridong Chen Project Summary Neuropathic pain can be difficult to treat with only 30-40% of patients achieving meaningful (>40-50%) pain relief. Current therapies (e.g. gabapentin) mainly address symptoms by focusing on blocking neurotransmission in the pain pathway with limited efficacy, potentially severe side effects and narrow therapeutic index. Thus, novel therapies are needed to safely manage symptoms and also target the underlying pathophysiological mech- anisms that will improve the functional status and life quality of affected patients. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of Treg by direct binding to its high affinity receptor that attenuates neuropathic pain. However, several drawbacks exist for current low-dose rIL2 therapy, including a short half life, propensity to in vitro aggregation causing adverse local reaction at injec- tion sites, and potentially narrow therapeutic window. We have designed a proprietary IL2-based therapy that will enable selective stimulation of Tregs with an extended half life, minimal in vitro aggregation, and broad ther- apeutic window. In the proposed Phase I SBIR study, we will evaluate the dose-response of the drug candidate in the rat model of CCI neuropathy. We also will determine the potential side effects and toxicity using the func- tional observational battery assays in healthy rats. Specific Aim. To determine whether rat IL2 analog will abrogate neuropathic pain in the CCI model in rats without behavioral side effects or toxicity. The long-term goal is to develop the drug candidate as a safe and disease-modifying analgesic therapy. Weekly dosing will provide sustained pain relief for neuropathic pain patients without significant side effects, tolerance or addiction.